Stroke is an enormous international public health concern, particularly in the developing world where there are limited resources available to provide for an aging population. One of the main contributors to stroke incidence is the highly prevalent Chagas disease, a parasitic infection affecting an estimated 18 million individuals and a major cause of heart failure in Latin America. Chagas disease conveys stroke risk through two established mechanisms: structural cardiac disease and chronic inflammation. Although inflammation is associated with an increased risk of ischemic stroke and poorer outcome, its role has been largely linked to atherogenesis. Chronic inflammation can result in endothelial dysfunction and stimulate the hemostatic system, increasing systemic fibrin production and platelet activation. Brain atrophy has also been associated with chronic inflammation. Adults, young and old, who develop a secondary cardiomyopathy from Chagas are therefore at higher risk of cardioembolism and neurodegeneration. Stroke patients usually survive, but can be left with significant disability affecting their health status, productivity, and quality of life. These factors impact caregivers as well. Thus, the social and economic consequences of stroke are vast. During our R21 planning grant period, we were able to establish a collaborative infrastructure between the research groups in Brazil and the United States and collect preliminary data. We found an association between Chagas disease and stroke that was independent of cardiomyopathy. Cognitive impairment and brain atrophy were also associated with Chagas disease independently of cardiomyopathy. Biomarkers orosomucoid, neprilysin, interleukin-6 (IL-6) and matrix metalloproteinase-9 (MMP-9) were identified as diagnostic and therapeutic targets in Chagas disease. As part of this phase, we will address three specific aims: (1) to establish brain magnetic resonance imaging markers of stroke risk in patients with Chagasic congestive heart failure (CM); (2) to determine whether biomarkers can predict stroke risk in patients with Chagasic CM; and (3) to evaluate the efficacy of antiplatelet treatment in decreasing microembolization rate in patients with Chagasic CM. The long-term goal of this project is to establish non-invasive methods of stroke risk stratification and prediction of stroke outcome in patients with Chagas disease. This work will also facilitate the development of novel anti-trypanosomal, anti- inflammatory, and antithrombotic strategies for stroke prevention and management in Brazil.